Disruption and resultant dysregulation of the SCL gene (TCL-5 or tal-1), either by chromosomal translocation or by a site-specific interstitial deletion, is the most common specific chromosomal aberration associated with T- cell acute lymphoblastic leukemia (ALL). Although the association of SCL gene disruption and T-cell ALL is striking, solid proof that SCL gene disruption leads to leukemia is lacking. This proposal outlines a series of studies to investigate the hypothesis that dysregulated SCL expression is a causal factor in malignant transformation. Classical transformation assays will be performed through transfection of SCL expression vectors into cell lines (Rat1A) or primary rate embryo cells. A transgenic mouse model for SCL associated leukemogenesis will be developed. This model is based on the observation that the most common form of SCL gene disruption results in the juxtaposition of SCL with an upstream gene, SIL. The net result of this SIL/SCL rearrangement is that expression of SCL (not normally expressed in T-cells) is aberrantly driven by the SIL promoter (normally active in T-cells). A series of experiments to characterize the SIL promoter and its regulatory elements is outlined. A construct which mimics the SIL/SCL rearrangement, with the SIL promoter driving expression of an SCL cDNA has been used to generate transgenic mice. These mice, while not yet developing T-cell malignancies, display a spectrum of developmental abnormalities. These transgenic mice will also be interbred with other transgenics to determine if they are prone to developing T-cell malignancies. IN addition, experiments investigating a potential role for SCL in apoptosis suppression are proposed. Furthermore, as the SIL/SCL rearrangement generates a SIL/SCL fusion mRNA, the possibility that an antisense SIL/SCL oligonucleotide inhibits the growth of cell lines which display the SIL/SCL rearrangement will be studied. SCL transactivation experiments, including the role of an alternatively spliced form of SCL lacking the activation domain, as proposed. The clinical relevance of these studies is twofold. First, an improved understanding of the role of SCL gene dysregulation in T-cell malignancies may identify targets for therapy. Second, given the observation that the SCL gene product is involved in normal hematopoiesis may lead to improved means of managing chemotherapy- related myelosuppression.